5. Elucidating the molecular mechanisms of small-molecule disruption of viral replication machinery Project Leader: Juan Perilla (CBC) Computational modeling and simulations provide a powerful toolset to determine the atomistic mechanisms underlying biological processes, such as those that occur during the life cycle of a pathogen. Likewise, computational methods can be leveraged to reveal the mechanisms by which these processes are altered or disrupted by small-molecule therapeutics. The work proposed here aims to elucidate the chemical and physical effects of small molecules on the replication machinery essential to a highly relevant human pathogen, namely HIV-1. Despite the success of several antiretrovirals, the virus has evolved resistance to all known drugs. Remarkably, not a single drug has been developed against large protein assemblies like the viral capsid therefore providing an unexploited therapeutic target. The work proposed here aims to elucidate the chemical and physical effects of small molecules on the capsid-related replication machinery essential to HIV. Importantly, the proposed work is not only relevant for HIV patients as HIV serves as a model for other human diseases, including virus-related cancer. In addition, the cutting-edge methods developed herein will be directly applicable to other virus and bacterial assemblies.